Novel pyrrolo[1,2-a][3.1.6]benzothiadiazocine ring synthesis. Unusual Truce-Smiles type rearrangement of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl] sulfonyl(or sulfinyl)}acetone

Article abstract of DOI:10.1016/j.tet.2004.07.036

Reaction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}acetone with sodium hydroxide with or without zinc gave 1-(2-nitrophenyl)(1H-pyrrol-2- ylsulfonyl)methane by a Truce-Smiles type of transformation and 1-(2-nitrophenyl)-2-methylsulfonylpyrrole by d

Full text of DOI:10.1016/j.tet.2004.07.036

Tetrahedron 60 (2004) 8807–8815
Novel pyrrolo[1,2-a][3.1.6]benzothiadiazocine ring synthesis.
Unusual Truce–Smiles type rearrangement of
1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl(or sulfinyl)}acetone
Athanasios Kimbaris,a Jonathan Cobb,b Georgios Tsakonasa and George Varvounisa,
*
aDepartment of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece
bDepartment of Chemistry, King’s College London, University of London, Strand, London WC2R 2LS, UK
Received 5 January 2004; revised 23 June 2004; accepted 15 July 2004
Available online 21 August 2004
Abstract—Reaction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}acetone with sodium hydroxide with or without zinc gave 1-(2-
nitrophenyl)(1H-pyrrol-2-ylsulfonyl)methane by a Truce–Smiles type of transformation and 1-(2-nitrophenyl)-2-methylsulfonylpyrrole by
deacetylation. Similar treatment of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfinyl}acetone gave only 1-(2-nitro-phenyl)(1H-pyrrol-2-
ylsulfinyl)methane. 1-{[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetone, 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}-1-phenyl-
ethan-1-one or 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetonitrile were reductively cyclised with sodium borohydride and 5%
palladium-on-carbon into 6-methyl(or phenyl)-5,6-dihydro-7H-pyrrolo[1,2-a][3.1.6]benzothiadiazocin-7-ol or 6-amino-5H-pyrrolo[1,2-
a][3.1.6]benzothiadiazocine-7-oxide, respectively.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
10H-pyrrolo[1,2-b][1.2.6]benzothiadiazocin-11-(12H)-
one-5,5-dioxide,12 was prepared by intramolecular
cyclisation of 2-{1-[(2-aminophenyl)sulfonyl]-1H-pyrrol-
2-yl}acetic acid. Fifteen years ago Cheeseman et al.
reported the synthesis of the 5,6-dihydropyrrolo[1,2-a]-
[3.1.6]benzothiadiazocine ring system.13,14 Two routes
were employed that utilized 1-(2-aminophenyl)-1H-pyr-
roles as starting materials. These compounds were derived
from the reaction between 2-nitroanilines and 2,5-
dimethoxytetrahydrofuran followed by reduction of the
resulting 1-(2-nitrophenyl)-1H-pyrroles. The first route
involved reaction of 1-(2-aminophenyl)-1H-pyrroles with
chloroacetic anhydride or a-chloropropionyl chloride,
thiocyanation of the N1-[2-(1H-pyrrol-1-yl)-phenyl]-2-
chloroacetamides with copper(II) thiocyanate and reductive
cyclisation of the resulting N1-[2-(2-thiocyanato-1H-pyrrol-
1-yl)phenyl)-2-chloroacetamides in the presence of sodium
borohydride.13 The second route involved treatment of 1-(2-
aminophenyl)-1H-pyrrole with trifluoroacetic anhydride,
thiocyanation of N1-[2-(1H-pyrrol-1-yl)-phenyl]-2,2,2-tri-
fluoroacetamide, reductive alkylation of N1-[2-(2-thiocya-
nato-1H-pyrrol-1-yl)-phenyl]-2,2,2-trifluoroacetamide with
ethyl bromoacetate and concomitant cleavage of the amide
group in the presence of sodium borohydride, followed
by cyclisation of the resulting ethyl 2-{[1-(2-aminophenyl)-
1H-pyrrol-2-yl]sulfanyl}acetate in the presence of
trimethylaluminium.14
Diaryl and arylheterocyclic sulfones are an emerging class
of non-nucleoside HIV-1 reverse transcriptase inhibi-
tors.1–10 Compounds with the sulfonyl group not part of a
ring seem to be the most potent, although related cyclic
counterparts such as 5H-pyrrolo[1,2-b][1.2.5]pyrrolobenzo-
thiadiazepin-11(10H)-one-5,5-dioxides6 are important
members of these bioactive compounds. Artico and co-
workers have recently synthesised 9H-pyrrolo[2,1-b]-
[1.3.6]benzothiadiazocin-10-(11H)-one-4,4-dioxide4 as a
potential anti-HIV-1 agent. The compound was prepared
by reacting 2-aminothiophenol with ethyl 2-(1H-pyrrol-1-yl)
acetate, hydrolysing ethyl 2-{2-[(2-amino-phenyl)sulfanyl]-
1H-pyrrol-1-yl}acetate, cyclising 2-{2-[(2-aminophenyl)-
sulfanyl]-1H-pyrrol-1-yl}acetic acid and oxidising 9H-pyr-
rolo[2,1-b][1.3.6]benzothiadiazocin-10-(11H)-one. The
synthesis of 10H-pyrrolo[1,2-b][1.2.5]benzothiadiazocine-
5,5-dioxide11 has been carried out by intramolecular
cyclisation of N-[2-(1H-pyrrol-1-ylsulfonyl)benzyl]metha-
namide, prepared from the reaction of [2-(1H-pyrrol-1-
ylsulfonyl)phenyl]methanamine with ethyl chloroformate,
followed by treatment with triphosgene. An isomer,
Keywords: Pyrroles; Pyrrolobenzothiadiazocines; Cyclisation; Reduction;
Truce–Smiles rearrangement.
* Corresponding author. Tel.: C30-26510-98382; fax: C30-26510-98799;
e-mail: gvarvoun@cc.uoi.gr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.036

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A. Kimbaris et al. / Tetrahedron 60 (2004) 8807–8815
2. Results and discussion
With an extension of this work in mind, we decided to
exploit the intramolecular capture of in situ generated
nitroso species by carbanions and the intramolecular
addition of hydroxyl-amines to carbonyl groups or nitriles
in order to effect ring closure by carbon–nitrogen bond
formation. To this end, we prepared ketones 2 and 3,14 ester
4 and nitrile 515 by selectively reducing 1-(2-nitrophenyl)-2-
thiocyanato-1H-pyrrole 115 with sodium borohydride and
then treating the resulting thiol, that was not isolated, with
2-chloroacetone, phenacyl bromide, ethyl bromoacetate or
chloroacetonitrile, respectively (Scheme 1).
Scheme 2. Reagents: (a) Zn, NH4Cl, H2O, EtOH, 0–22 8C.
A few examples, where intramolecular capture of in situ
generated nitroso species is used for the synthesis of fused
heterocycles, are given below. Reductive cyclisation of N1-
(alkyl or aryl)-2-nitrobenzamides into 2-(alkyl or aryl)-2,3-
dihydro-1H-3-indazolones has been accomplished via
treatment with zinc dust and sodium hydroxide.16 Milder
reaction conditions, zinc dust and ammonium chloride, have
been used for the cyclisation of substituted 3-(2-nitro-
phenoxy)phenols to 3H-phenoxazin-3-ones17 and of ethyl
2-nitrophenylacetate to 4-hydroxy-1,4-benzoxazine-3(4H)-
one.18 Recently, we reported the reductive cyclisation of
(2-nitrophenyl)(1H-pyrrol-2-yl)methanone with zinc and
ammonium chloride or sodium hydroxide which gave
5,10-dihydropyrrolo[1,2-b]cinnolin-10-one.19
chloride failed, yielding instead the amine 14 and nitroso
compound 16, respectively.
We anticipated that by using a stronger base such as sodium
hydroxide in the reduction of sulfone 13, the abstraction of
the relatively acidic methylene proton should be accelerated
according to the mechanism of Scheme 2, and would lead to
the sulfone derivative of pyrrolobenzothiadiazepine 6 (RZ
COMe). However, heating 13 in aqueous ethanolic sodium
hydroxide containing zinc dust yielded a mixture of two
new compounds, 21 and 25, in 48 and 43% yield,
respectively. A speculative mechanism for this reaction is
shown in Scheme 4. In line with the proposed mechanism,
hydroxide ion could react on compound 13 both as a base
and as a nucleophile. Intramolecular nucleophilic attack on
the benzene ring by carbanion 17 would give the
Meisenheimer-type intermediate 18 that could ring-open
prior or after addition of hydroxide anion to the acetyl group
to give, after loss of acetate anion, pyrrolyl dianion 19. On
the other hand, addition of hydroxide ion to the acetyl group
of 13 would give intermediate 22 from which loss of acetate
anion would lead to carbanion 23. After acidification, the
reaction would lead to products 21 and 25. The formation of
21 is considered to be an unusual case of a Truce–Smiles
rearrangement. The reason that the nitro groups of
compounds 21 and 25 are not reduced by the reductive
reaction conditions is probably due to the rapid interconver-
sion between 19 and 21 and 23 and 25, before acidification.
The structure of 25 was confirmed by its unambiguous
synthesis from thiocyanate 1. The latter was alkylated with
methyl iodide in the presence of sodium borohydride to give
1-(2-nitrophenyl)-2-methylthio-1H-pyrrole, which was then
oxidised directly to sulfone 25 by reaction with oxonew in
acetone at room temperature. Heating compound 13 in
aqueous ethanolic sodium hydroxide gave a mixture of 21
and 25 in 46 and 41%yield, respectively. Furthermore when
compounds 21 and 25 were heated in aqueous sodium
hydroxide with or without the presence of zinc dust, starting
material was recovered unchanged. These results confirm
beyond doubt that zinc dust plays no role in the reaction and
that the formation of 21 and 25 occurs independently from
13. Cheeseman and Hawi have proposed a mechanism
similar in some respects to that of Scheme 4 to explain the
rearrangement of methyl 2-{[1-(2-nitrophenyl)-1H-pyrrol-
2-yl]thio}acetate into 2,3-dihydro-2-(2-nitrophenyl)-3-oxo-
pyrrolo[2,1-b]thiazole. The reaction took place in dimethyl
sulfoxide with potassium t-butoxide as base.15
Selective reduction of compounds 2, 3 and 4 with zinc dust
and ammonium chloride in aqueous ethanol from 0 8C to
room temperature respectively afforded mixtures of the
corresponding amines 7, 914 and 11,14 and hydroxylamines
8, 10 and 12 (Scheme 2). No trace of the anticipated
pyrrolobenzothiadiazepines 6 was detected. This could be
due to the weakly basic reaction conditions that were
ineffective in deprotonating the methylene group in the
intermediate nitroso compounds. On the other hand when
compounds 2 and 3 were subjected to selective reduction
using zinc dust and sodium hydroxide in refluxing aqueous
ethanol, a complex mixture was produced in each case that
appeared as a streak on TLC. All attempts to separate the
components of these mixtures proved unsuccessful.
Oxidation of 2 and 3 to their sulfones would increase the
acidity of the methylene hydrogens in these compounds.
Thus, compounds 2 and 3 were oxidized smoothly into their
corresponding sulfones 13 and 15 by 2-chloroperbenzoic
acid (Scheme 3). However, the required reductive cyclisa-
tion of 13 and 15 by treatment with zinc and ammonium
Scheme 1. Reagents: (a) (i) NaBH4, EtOH, NaOH, (ii) ClCH2COMe,
BrCH2COPh, BrCH2CO2Et or ClCH2CN.

A. Kimbaris et al. / Tetrahedron 60 (2004) 8807–8815
8809
Scheme 3. Reagents: (a) 3-chloroperbenzoic acid, CH2Cl2, reflux; (b) Zn, NH4Cl, H2O, EtOH, 0–22 8C.
Scheme 4. Reagents: (a) Zn, NaOH, H2O, EtOH, reflux; (b) NaOH, H2O, EtOH, reflux.
In order to acquire further insight into the reaction of
Scheme 4 it was decided to prepare sulfoxide 26. The first
attempt involved the oxidation of sulfide 2 by 3-chloro-
perbenzoic acid at room temperature for several days. This
however resulted in a mixture of starting material and
sulfoxide 26 but reaction of 2 with oxonew in acetone at
ambient temperature afforded sulfoxide 26 as a single
product in 88% yield (Scheme 5). When 26 was heated in
aqueous ethanolic sodium hydroxide containing zinc dust
pyrrolylsulfinylmethane 27 was obtained in 68% yield.
Repeating the reaction without zinc dust gave 27 in 72%
yield. An analogous mechanism to that described for the
transformation of 13 to 21 in Scheme 4 is proposed. A likely
explanation for 1-(2-nitrophenyl)-2-methylsulphinylpyrrole
not being formed is that the sulfoxide analogue of carbanion
23 (Scheme 4) is less stabilised than 23 itself and is
therefore not formed.
Compounds 2, 3 and 5 were found to be useful precursors to
the novel pyrrolo[1,2-a][3.1.6]benzothiadiazocin-7-ols 31
and 32, and, pyrrolo[1,2-a][3.1.6]benzothiadiazocine-7-
oxide 36, respectively. Thus ketones 2 or 3 were reductively
cyclised in the presence of sodium borohydride and 5%
palladium-on-carbon to give the corresponding tricycles 31
and 32 in 51 and 56% yield respectively (Scheme 6). It is
proposed that the initial step in this reaction is reduction of
both nitro and keto groups of compounds 2 or 3 leading
intermediate 28. After addition of ethanolic hydrogen
chloride, protonation of 28 gives intermediate 29. The latter
may deprotonate back to 28 or intramolecularly cyclise to
30 by displacement of water. Loss of a proton from
intermediate 30 gives either 31 or 32.
In the 1H NMR spectrum of 31 at 24 8C, the broad signal at
2.24 ppm contains the upfield signal of the methylene

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A. Kimbaris et al. / Tetrahedron 60 (2004) 8807–8815
Scheme 5. Reagents: (a) oxonew, (Me)2CO, 30 min; (b) Zn, NaOH, H2O, EtOH, reflux; (c) NaOH, H2O, EtOH, reflux.
Scheme 6. Reagents: (a) (i) NaBH4, 10% Pd–C, H2O, 1,4-dioxane, 2% aq. NaOH, (ii) EtOH–HCl, pHZ5–6.
group, assigned to H-5a, overlapping with the hydroxyl
group. This was verified by D2O addition which showed a
remaining broad signal at 2.24 ppm. H-5b appears as a
doublet at 2.48 ppm and H-6 appears as a multiplet in the
region 3.65–3.70. Line narrowing is known to occur when
the conformational equilibrium of a methylene group is fast
on the NMR time-scale.20 The fine structure of these signals
was revealed by recording the spectrum at 60 8C. At this
temperature the OH signal shifted upfield by 0.22 ppm,
H-5a and H-5b are double doublets at 2.35 and 2.51 ppm,
respectively, and H-6 is a double doublet of a quartet at
3.69 ppm. In the 1H NMR spectrum of 32 at 24 8C, the broad
signal at 2.50 ppm, assigned to H-5a, overlaps with the
hydroxyl group. After D2O addition the remaining signal at
2.50 ppm is broad. H-5b and H-6 appear as double doublets
at 2.69 and 4.57 ppm, respectively. In the spectrum of 32 at
60 8C, H-5a has sharpened to a double doublet at 2.55 ppm
whereas the OH signal is so broad that its chemical shift
cannot be recorded.
Treatment of nitrile 5 with sodium borohydride and 5%
palladium-on-carbon gave tricyclic-N-oxide 36 in 43%
yield (Scheme 7). The proposed mechanism for this
transformation involves reduction of 5 to intermediate
hydroxylamine 33, intramolecular nucleophilic addition to
the nitrile group, protonation of resulting imine 34 to
iminium cation 35 and conversion of the later to N-oxide 36
by lone pair electron delocalisation and deprotonation. The
Scheme 7. Reagents: (a) (i) NaBH4, 10% Pd–C, H2O, 1,4-dioxane, 2% aq. NaOH, (ii) EtOH/HCl, pHZ5–6.

A. Kimbaris et al. / Tetrahedron 60 (2004) 8807–8815
8811
carbon and proton atoms of compounds 31, 32 and 36 were
fully characterised with the aid of DQF-COSY, DEPT,
HMQC and HMBC spectra.
dichloromethane (3!15 mL). The combined organic
extracts were dried (Na2SO4) and the solvent was
evaporated under reduced pressure. The residue was
purified by flash chromatography (12, 25% ethyl acetate/
light petroleum) to give 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-
yl]sulfanyl}acetone 2, 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-
yl]sulfanyl}-1-phenylethan-1-one 3, ethyl 2-{[1-(2-nitro-
phenyl)-1H-pyrrol-2-yl]sulfanyl}acetate 4 or [1-(2-nitro-
phenyl)-1H-pyrrol-2-ylsulfanyl]acetonitrile 5, respectively.
In summary, it has been shown that substituted pyrroles
such as 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}ace-
tone are reduced by zinc and ammonium chloride to the
corresponding hydroxylamine and amine derivatives, with-
out the observation of any intramolecular interaction. A
similar result was obtained with 1-{[1-(2-nitro-phenyl)-1H-
pyrrol-2-yl]sulfonyl}acetone where only the corresponding
amine was isolated. However, treatment of 1-{[1-(2-
nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}acetone with zinc
and sodium hydroxide gave a mixture of two products
resulting from a Truce–Smiles type of transformation and a
simple deacetylation. Remarkably, no reduction of the nitro
group in these compounds had occurred. Reduction of
1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}acetone or
-1-phenylethan-1-one with sodium borohydride and 5%
palladium-on-carbon, lead to two novel pyrrolo[1,2-a]-
[3.1.6]benzothiadiazocine derivatives. The N-oxide func-
tion of these compounds suggests transient hydroxyl-amine
intermediates This novel synthetic method was successfully
applied.
3.2.1. 1-{[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}-
acetone (2). (0.5 g, 72%) as pale yellow oil, bp 112–
114 8C/12 mm Hg; nmax(liquid film) 1720, 1540, 1360 cmK1
;
dH (360 MHz; CDCl3) 2.07 (3H, s, Me), 3.12 (1H, s, br,
CH2), 6.33 (1H, dd, JZ3.6, 3.1 Hz, H-4), 6.59 (1H, dd, JZ
3.6, 1.7 Hz, H-3), 6.88 (1H, dd, JZ3.1, 1.7 Hz, H-5), 7.50
(1H, dd, JZ7.9, 1.3 Hz, H-60), 7.61 (1H, ddd, JZ9.0, 8.0,
1.3 Hz, H-40), 7.74 (1H, ddd,0JZ9.0, 7.9, 1.6 Hz, H-50), 8.05
(1H, dd, JZ8.0, 1.6 Hz, H-3 ); dC (90.5 MHz; CDCl3) 28.3,
47.3, 110.9, 120.3, 120.8, 125.1, 125.9, 129.3, 131.2, 132.9,
133.5, 146.6, 202.9; m/z (EI) 276 (65, MC), 260 (10) 187
(33), 171 (38), 143 (12), 83 (100%); HRMS (EI): (MC),
found 276.0563. C13H12N2O3S requires 276.0569.
3.2.2. 2-{[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}-1-
phenylethan-1-one (3). (1.27 g, 76%) as yellow needles
(ethanol); mpZ96–97 8C; (lit.14 mpZ97–98 8C), identical
in all respects to an authentic sample.
3. Experimental
3.1. General methods
3.2.3. Ethyl 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfa-
nyl}acetate (4). (0.68 g, 49%) as a yellow oil, bp 123–
Melting points were taken on a Bu¨chi 510 apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin–
Elmer 257 spectrometer, as Nujol mulls and liquids between
sodium chloride discs. Elemental analyses were performed
on a Carlo Erba 1106 elemental analyser. Nuclear magnetic
resonance spectra were measured at 360 MHz on a Bru¨ker
AM 360 spectrometer or at 400 MHz on a Bru¨ker AMX 400
spectrometer using tetramethylsilane as internal standard.
Mass spectra were obtained using a JEOL JMS-AX 505W
high resolution instrument under EI or CI conditions, or a
Bruker Apex III high resolution instrument under ESI
conditions. Analytical TLC was carried out on Fluka silica
gel 60 F254. Preparative flash chromatography was carried
out using Merck 9385 silica gel. Solvents and reagents were
used as received from the manufacturers except for
dichloromethane, ethanol, ethyl acetate, light petroleum
(bp 40–60 8C) and methanol that were purified and dried
according to recommended procedures.21
128 8C/12 mm Hg; nmax (liquid film) 1740, 1540, 1350 cmK1
;
dH (400 MHz; CDCl3) 1.20 (3H, t, JZ7.0 Hz, Me), 3.03
(2H, d, JZ7.8, Hz, SCH2), 4.01–4.12 (2H, m, CH2), 6.35
(1H, dd, JZ3.3, 3.0 Hz, H-4), 6.67 (1H, dd, JZ3.3, 1.7 Hz,
H-3), 6.89 (1H, 0dd, JZ3.0, 1.7 Hz, H-5), 7.48 (1H, dd, JZ
7.8, 1.4 Hz, H-6 ), 7.60 (1H, ddd, JZ8.1, 7.9, 1.5 Hz, H-40),
7.71 (1H, ddd, JZ7.9, 7.8, 1.5 Hz, H-50), 8.04 (1H, dd, JZ
8.1, 1.5 Hz, H-30); dC (100 MHz; CDCl3) 12.8, 33.8, 60.3,
106.3, 115.9, 117.7, 119.0, 124.4, 125.3, 126.5, 128.0,
131.2, 142.8, 171.4; m/z (EI) 306 (35, MC), 275 (68), 173
(100), 140 (25%); HRMS (EI): (MC), found 306.0671
C14H14N2O4S requires 306.0674.
3.2.4. [1-(2-Nitro-phenyl)-1H-pyrrol-2-ylsulfanyl]aceto-
nitrile (5). (0.76 g, 62%) as pale yellow oil; (lit.15), identical
in all respects to an authentic sample.
3.3. Reduction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-
sulfanyl}acetone, 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-
sulfanyl}-1-phenylethan-1-one and ethyl 2-{[1-(2-nitro-
phenyl)-1H-pyrrol-2-yl]sulfanyl}acetate with zinc dust
and ammonium chloride in aqueous ethanol. General
procedure B
3.2. Alkylation of 1-(2-nitrophenyl)-1H-pyrrol-2-ylthio-
cyanate. General procedure A
To a stirred solution of 1 (1.22 g, 5 mmol) in dry ethanol
(50 mL), kept under a continuous stream of argon, sodium
borohydride (0.28 g, 7.5 mmol) was added in portions and
the mixture stirred at room temperature for 45 min. A
solution of sodium hydroxide (0.42 g, 7.5 mmol) in dry
ethanol (10 mL) was then added followed by chloro-
acetone, phenacyl bromide, ethyl chloroacetate or chloro-
acetonitrile (7.5 mmol). The mixture was stirred at
60–65 8C for 1.5 h and at room temperature for 12 h. The
solvent was removed in vacuo up to 15 mL and to this oily
residue, water (45 mL) was added and extracted with
To a stirred solution of compounds 2, 3 or 4 (1.2 mmol) in
ethanol (15 mL) at 0 8C was added zinc dust (0.24 g,
3.6 mmol) followed by a solution of ammonium chloride
(0.38 g, 7.2 mmol) in water (8 mL). The reaction mixture
was left to stir at room temperature for 1.5 h, filtered the
residue washed with hot ethanol (15 mL). The solvents were
evaporated in vacuo to near dryness, water (35 mL) was
added and extracted with dichloromethane (3!10 mL). The

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A. Kimbaris et al. / Tetrahedron 60 (2004) 8807–8815
combined organic extracts were dried (Na2SO4) and the
solvent removed under reduced pressure. The oily residue
was purified by flash chromatography (12% ethyl acetate/
light petroleum) to give two fractions. The first fraction
gave 1-{[1-(2-aminophenyl)-1H-pyrrol-2-yl]sulfanyl}ace-
tone 7, 2-{[1-(2-aminophenyl)-1H-pyrrol-2-yl]-sulfanyl}-
1-phenylethan-1-one 9 or ethyl 2-{[1-(2-aminophenyl)-
1H-pyrrol-2-yl]sulfanyl}acetate 11 and the second fraction
gave 1-{[1-(2-hydroxylaminophenyl)-1H-pyrrol-2-yl]sul-
fanyl}acetone 8, 2-{[1-(2-hydroxylaminophenyl)-1H-pyrrol-
2-yl]sulfanyl}-1-phenylethan-1-one 10 or ethyl 2-{[1-(2-
hydroxylaminophenyl)-1H-pyrrol-2-yl]sulfanyl}acetate 12,
respectively.
3.3.5. Ethyl 2-{[1-(2-aminophenyl)-1H-pyrrol-2-yl]sulfa-
nyl}acetate (11). (0.12 g, 37%) as an oil (lit.14), identical in
all respects to an authentic sample.
3.3.6. Ethyl 2-{[1-(2-hydroxylaminophenyl)-1H-pyrrol-
2-yl]sulfanyl}acetate (12). (0.17 g, 49%) as pale yellow oil,
bp 151–154 8C/12 mm Hg; nmax (liquid film) 2430,
1760 cmK1; dH (400 MHz; CDCl3) 1.19 (3H, t, JZ7.1 Hz,
Me) 3.04 (2H, d, JZ7.8 Hz, SCH2), 4.02 (2H, q, CH2), 5.5
(2H, s, br, NHOH), 6.29 (1H, t, JZ3.3 Hz, H-4), 6.57 (1H,
dd, JZ3.3, 1.8 Hz, H-3), 6.86 (1H, dd, JZ3.3, 1.8 Hz, H-5),
7.03 (1H, ddd, JZ8.0, 7.0, 2.2 Hz, H-50), 7.17 0(1H, dd, JZ
7.8, 2.2 Hz, H-30), 7.38–7.42 (2H, m, H-4 , H-60); dC
(100 MHz; CDCl3) 12.9, 33.7, 60.3, 105.1, 115.1, 116.2,
116.5, 118.5, 122.3, 126.9, 128.0, 129.5, 140.4, 171.4; m/z
(EI) 292 (14, MC), 276 (67), 187 (57), 173 (100), 156 (70),
140 (20), 119 (10%); HRMS (EI): (MC), found 292.0888.
C14H16N2O3S requires 292.0882.
3.3.1. 1-{[1-(2-Aminophenyl)-1H-pyrrol-2-yl]sulfanyl}a-
cetone (7). (90 mg, 31%) as pale yellow oil, bp 152–155 8C/
12 mm Hg; nmax (liquid film) 3525, 3420, 1685 cmK1; dH
(400 MHz; CDCl3) 2.29 (3H, s, Me), 3.69 (2H, s, br, NH2),
3.71 (2H, d, JZ13 Hz, SCH2), 6.27 (1H, t, JZ3.6 Hz, H-4),
6.81 (1H, d0d, JZ3.6, 1.8 Hz, H-3), 6.91 (1H, dd, JZ7.9,
1.4 Hz, H-3 ), 7.11 (1H, dd, JZ03.6, 1.8 Hz, H-5), 7.29 (1H,
ddd, JZ9.0, 7.9, 1.4 Hz, H-5 ), 7.48 (1H, ddd, JZ7.9,
1.3 Hz, H-40), 7.52 (1H, dd, JZ9.0, 1.3 Hz, H-60); dC
(100 MHz; CDCl3) 28.8, 41.7, 106.2, 115.6, 116.5, 116.8
(2C), 126.4 (2C), 128.7, 129.5, 202.2; m/z (EI) 246 (63,
MC), 229 (18) 153 (75), 69 (100%); HRMS (EI): (MC),
found 246.0826. C13H14N2OS requires 246.0833.
3.4. Oxidation of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]
sulfanyl}acetone and 2-{[1-(2-nitrophenyl)-1H-pyrrol-
2-yl]sulfanyl}-1-phenylethan-1-one with 2-chloro-
perbenzoic acid. General procedure C
To a solution of compound 2 or 3 (1.45 mmol) in
dichloromethane (30 mL) was added 2-chloroperbenzoic
acid (0.25 g, 1.45 mmol) and the resulting mixture was
heated under reflux for 12 h. Heating was continued for 10 h
during which time 2-chloroperbenzoic acid (0.03 g,
0.15 mmol) was added at hourly intervals. The solvent
was evaporated under reduced pressure and to the oily
residue water (30 mL) was added and the mixture extracted
with dichloromethane (3!10 mL). The combined organic
extracts were dried (Na2SO4) and the solvent removed in
vacuo. Purification of the oily residue by flash chromato-
graphy (11%, 50% ethyl acetate/light petroleum) afforded
1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}acetone 13
or 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}-1-phenyl-
ethan-1-one 15.
3.3.2. 1-{[1-(2-Hydroxylaminophenyl)-1H-pyrrol-2-yl]-
sulfanyl}acetone (8). (0.13 g, 43%) as pale yellow oil, bp
143–145 8C/12 mm Hg; nmax (liquid film) 3380, 1710 cmK1
;
dH (400 MHz; CDCl3) 2.07 (3H, s, Me), 3.18 (2H, s, SCH2),
5.62 (2H, s, br, NHOH), 6.28 (1H, t, JZ3.1 Hz, H-4), 6.48
(1H, dd, JZ3.1, 1.4 Hz, H-3), 6.87 (1H, dd, JZ3.1, 1.4 Hz,
H-5), 6.97 (1H, ddd, JZ8.0, 7.2, 2.4 Hz, H-50), 7.16 (1H,
dd, JZ7.8, 2.4 Hz, H-30), 7.52 (1H, ddd, JZ7.80, 7.2,
1.4 Hz, H-40), 7.79 (1H, dd, JZ8.0, 1.4 Hz, H-6 ); dC
(100 MHz; CDCl3) 28.7, 41.8, 106.3, 110.7, 117.1, 118.3,
122.2, 126.5, 128.2, 129.0, 140.1, 202.1; m/z (EI) 263 (45,
MC), 188 (58) 169 (65), 83 (100%); HRMS (EI): (MC),
found 263.0854. C13H14N2O2S requires 263.0845.
3.4.1. 1-{[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}-
acetone (13). (0.33 g, 74%) as a yellow oil, bp 159–
162 8C/12 mm Hg; nmax (liquid film) 1710, 1545, 1340,
1290, 1140 cmK1; dH (400 MHz; CDCl3) 2.30 (3H, s, Me),
3.84 (1H, d, JZ13.2 Hz, HCH), 4.06 (1H, d, JZ13.2 Hz,
HCH) 6.45 (1H, dd, JZ3.9, 2.8 Hz, H-4), 6.96 (1H, dd, JZ
3.9, 2.2 Hz, H-3), 7.14 (1H, dd, JZ3.9, 2.2 Hz, H-5), 7.63
(1H, dd, JZ7.6, 1.5 Hz, H-60), 7.70 (1H, ddd, JZ8.0, 7.6,
1.5 Hz, H-40), 7.75 (1H, ddd, 0JZ8.0, 7.6, 1.6 Hz, H-50), 8.14
(1H, dd, JZ8.0, 1.6 Hz, H-3 ); dC (100 MHz; CDCl3) 31.0,
65.7, 111.4, 114.5, 125.3, 128.0, 130.5, 131.3, 131.5, 133.8,
134.2, 146.4, 199.3; m/z (EI) 308 (1, MC), 279 (10) 235 (3),
210 (13), 188 (42), 168 (53), 143 (40), 129 (47), 102 (63), 83
(100%); HRMS (EI): (MC), found 308.0454. C13H12N2O5S
requires 308.0466).
3.3.3. 2-{[1-(2-Aminophenyl)-1H-pyrrol-2-yl]sulfanyl}-
1-phenylethan-1-one (9). (0.12 g, 34%) as an oil (lit.14),
identical in all respects to an authentic sample.
3.3.4. 2-{[1-(2-Hydroxylaminophenyl)-1H-pyrrol-2-yl]-
sulfanyl}-1-phenylethan-1-one (10). (0.22 g, 58%) as a
pale yellow oil, bp 168–172 8C/12 mm Hg; nmax (liquid
film) 3400, 1680 cmK1; dH (400 MHz; CDCl3) 3.53 (1H, d,
JZ12.4 Hz, HCH), 3.69 (1H, d, JZ12.4 Hz, HCH), 5.83
(2H, s, br, NHOH), 6.26 (1H, t, JZ3.3 Hz, H-4), 6.38 (1H,
dd, JZ3.3, 1.4 Hz, H-3), 6.86 (1H, dd, JZ3.3, 1.4 Hz, H-5),
6.98 (1H, dd, JZ7.1, 2.4 Hz, benzenoid), 7.15 (1H, d, JZ
7.6 Hz, benzenoid), 7.37–7.44 (5H, m, benzenoid), 7.55
(1H, d, JZ7.5 Hz, benzenoid), 7.82 (1H, dd, JZ7.6, 1.4 Hz,
benzenoid); dC (100 MHz; CDCl3) 37.8, 115.8, 116.1,
116.9, 118.4, 119.2, 122.4, 126.7 (2C), 128.6 (2C), 130.4
(2C), 131.8, 132.2, 134.6, 142.2, 193.5; m/z (EI) 324 (3,
MC), 281 (39), 267 (22), 221 (49), 187 (67), 147 (100), 133
(21%); HRMS (EI): (MC), found 324.0937. C18H16N2O2S
requires 324.0932.
3.4.2. 2-{[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}-1-
phenylethan-1-one (15). (0.36 g, 68%) as colourless plates
(ethyl acetate); mp 143–144 8C [Found: C, 58.31; H, 3.85;
N, 7.61. C18H14N2O5S requires C, 58.37; H, 3.81; N,
7.57%]; nmax (liquid film) 1680, 1540, 1340, 1325,
1240 cmK1; dH (400 MHz; CDCl3) 3.84 (1H, d, JZ
13.1 Hz, HCH), 4.28 (1H, d, JZ13.1 Hz, HCH), 6.32 (1H,

A. Kimbaris et al. / Tetrahedron 60 (2004) 8807–8815
8813
t, JZ3.3 Hz, H-4), 6.81–6.84 (2H, m, H-3, benzenoid), 7.15
(1H, dd, JZ3.3, 1.8 Hz, H-5), 7.35–7.39 (5H, m, benze-
noid), 7.52 (1H, d, JZ7.4 Hz, benzenoid), 7.72 (2H, m,
benzenoid); dC (100 MHz; CDCl3) 47.8, 117.2, 117.9,
119.8, 120.9, 124.1, 128.0, 130.0, 130.3 (2C), 130.6, 131.1
(2C), 133.2, 134.9, 135.3, 144.8, 180.7; m/z (EI) 370 (14,
MC), 317 (18), 267 (26), 198 (100), 155 (60), 113 (72%).
nitrophenyl)-1H-pyrrol-2-yl]sulfinyl}acetone 26 (0.36 g,
88%) as an orange oil, bp 147–152 8C/12 mm Hg; nmax
(liquid film) 1710, 1520, 1330, 1220 cmK1; dH (400 MHz;
CDCl3) 2.15 (3H, s, Me) 3.86 (1H, d, JZ14.2 Hz, HCH),
3.94 (1H, s, br, HCH), 6.39 (1H, t, JZ3.3 Hz, H-4), 6.82
(1H, s,0H-3),0 6.89 0(1H, d, JZ3.3 Hz, H-5), 7.59–7.72 (3H,
m, H-4 , H-5 , H-6 ). 7.99 (1H, d, JZ8.0 Hz, H-30); m/z (EI)
293 (75, MCC1), 277 (53), 235 (100), 188 (65%); HRMS
(EI): (MC), found 292.0525. C13H12N2O4S requires
292.0518.
3.5. Reduction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-
yl]sulfonyl}acetone and 2-{[1-(2-nitrophenyl)-1H-pyr-
rol-2-yl]sulfonyl}-1-phenylethan-1-one with zinc dust
and ammonium chloride in aqueous ethanol
3.6. Reaction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-
sulfonyl}acetone and 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-
yl]sulfinyl}acetone with zinc dust and sodium hydroxide
in aqueous ethanol. General procedure D
Compound 13 or 15 (0.9 mmol) was dissolved in ethanol
(10 mL), the solution cooled to 0 8C and treated with zinc
dust (0.18 g, 2.7 mmol) and ammonium chloride (0.29 g,
5.4 mmol) according to General procedure B. The oily
residue after work-up was purified by column chromato-
graphy (33% ethyl acetate/light petroleum) to give 1-{[1-(2-
aminophenyl)-1H-2-pyrrol-2-yl]sulfonyl}acetone 14 or
2-{[1-(2-nitrosophenyl)-1H-pyrrol-2-yl]-sulfonyl}-1-phe-
nylethan-1-one 16.
To a stirred solution of 13 or 26 (1.2 mmol) in ethanol
(15 mL) was added a solution of sodium hydroxide (0.19 g,
4.8 mmol) in water (8 mL) and zinc dust (0.24 g, 3.6 mmol).
The resulting mixture was heated under reflux over a period
of 3 h, filtered, washed with hot ethanol and the filtrate
evaporated to near dryness. Water (35 mL) was added to the
oily residue and then extracted with dichloromethane (3!
10 mL). The combined organic extracts were dried
(Na2SO4), evaporated in vacuo, and the oily residue was
purified by column chromatography (12% ethyl acetate/
light petroleum) to give in the first fraction 1-(2-nitrophe-
nyl)(1H-pyrrol-2-ylsulfonyl)methane 21 and in the second
fraction 1-(2-nitrophenyl)-2-methylsulfonylpyrrole 25 or
(ethyl acetate) to give 1-(2-nitrophenyl)(1H-pyrrol-2-ylsul-
finyl)methane 27.
3.5.1. 1-{[1-(2-Aminophenyl)-1H-2-pyrrol-2-yl]sulfon-
yl}acetone (14). (0.18 g, 73%) as colourless needles
(ethanol); mp 100–101 8C; [Found: C, 56.16; H, 4.99; N,
10.02. C13H14N2O3S requires C, 56.10; H, 5.07; N,
10.07%]; nmax (Nujol) 3460, 3360, 1705, 1320, 1125 cmK1
;
dH (400 MHz; CDCl3) 2.29 (3H, s, Me), 3.91 (2H, s, br,
NH2), 4.14 (2H, s, CH2), 6.33 (1H, dd, JZ3.9, 2.6 Hz, H-4),
6.87 (1H, d0d, JZ2.6, 1.8 Hz, H-3), 6.91 (1H, dd, JZ7.9,
1.4 Hz, H-3 ), 7.11 (1H, dd, JZ3.9, 1.8 Hz, H-5), 7.28 (1H,
ddd, JZ8.8,07.9, 1.4 Hz, H-50), 7.47 (1H, ddd, JZ8.8, 7.7,
1.3 Hz, H-4 ), 7.52 (1H, dd, JZ7.9, 1.3 Hz, H-60); dC
(100 MHz; CDCl3) 31.0, 57.8, 109.3, 112.7, 113.3, 116.9,
117.6, 125.49, 126.2, 128.1, 131.4, 140.1, 197.1; m/z (EI)
278 (75, MC), 221 (62), 169 (100), 142 (35%).
3.6.1.
1-(2-Nitrophenyl)(1H-pyrrol-2-ylsulfonyl)-
methane (21). (0.15 g, 48%) as colourless needles (tolu-
ene); mp 116–118 8C; [Found: C, 49.57; H, 3.81; N, 10.57.
C11H10N2O4S requires C, 49.62; H, 3.79; N, 10.52%]; nmax
(Nujol) 3440, 1550, 1365, 1345, 1135 cmK1; dH (400 MHz;
CDCl3) 4.99 (2H, s, CH2), 6.26 (1H, dd, JZ3.8, 2.8 Hz, H-
4), 6.60 (1H, dd, JZ3.8, 2.6 Hz, H-3), 6.97 (1H,0dd, JZ2.8,
2.6 Hz, H-5), 7.39 (1H, dd, JZ7.5, 1.6 Hz, H-6 ) 7.54 (1H,
ddd, JZ9.0, 8.0, 1.6 Hz, H-40), 7.59 (1H, ddd, 0JZ9.0, 7.5,
1.5 Hz, H-50), 7.99 (1H, dd, JZ8.0, 1.5 Hz, H-3 ), 9.18 (1H,
s, br, NH); dC (90.5 MHz; CDCl3) 59.07, 110.4, 116.8,
123.4, 124.1, 124.9, 125.3, 129.8, 133.1, 134.0, 149.4; m/z
(EI) 266 (28, MC), 185 (37), 154 (16), 130 (75), 78 (100%);
HRMS (EI): (MC), found 266.0358. C11H10N2O4S requires
266.0361.
3.5.2. 2-{[1-(2-Nitrosophenyl)-1H-pyrrol-2-yl]sulfonyl}-
1-phenylethan-1-one (16). (0.25 g, 77%) as pale-yellow
solid (ethyl acetate/hexane); mp 49–50 8C; nmax (Nujol)
1670, 1320, 1100 cmK1; dH (400 MHz; CDCl3) 4.31 (1H, d,
JZ13.0 Hz, HCH), 4.44 (1H, d, JZ13.0 Hz, HCH), 6.33
(1H, t, JZ3.4 Hz, H-4), 6.81–6.84 (2H, m, H-3, benze-
noid,), 6.96 (1H, s, br, benzenoid), 7.16 (1H, s, br, H-5),
7.35–7.40 (4H, m, benzenoid), 7.52 (1H, t, JZ7.3 Hz,
benzenoid), 7.71 (2H, s, br, benzenoid); dC (100 MHz;
CDCl3) 53.7, 112.8, 116.5, 119.6, 120.1, 121.6, 124.3,
127.5, 130.1, 130.3 (2C), 130.7, 131.2 (2C), 134.2, 134.9,
145.8, 188.7; m/z (EI) 355 (1, MCC1), 323 (24), 272 (74),
257 (70), 218 (59), 187 (50), 156 (80), 131 (55), 105 (100),
69 (98%); HRMS (EI): (MCC1), found 355.0730.
C18H15N2O4S requires 355.0752.
3.6.2. 1-(2-Nitrophenyl)-2-methylsulfonylpyrrole (25).
(0.15 g, 43%) as colourless needles (toluene); mp 90–
92 8C; [Found: C, 49.66; H, 3.75; N, 10.59. C11H10N2O4S
requires C, 49.62; H, 3.79; N, 10.52%]; nmax (Nujol) 1540,
1330, 1310, 1140 cmK1; dH (400 MHz; CDCl3) 2.93 (3H, s,
Me), 6.43 (1H, dd, JZ3.9, 2.8 Hz, H-4), 6.86 (1H, dd, JZ
2.8, 1.9, Hz, H-3), 7.13 (1H, 0dd, JZ3.9, 1.9 Hz, H-5), 7.63
(1H, dd, JZ7.7, 1.5 Hz, H-6 ), 7.68 (1H, ddd, JZ8.0, 6.3,
1.5 Hz, H-40), 7.74 (1H, ddd, 0JZ7.7, 6.3, 1.5 Hz, H-50), 8.09
(1H, dd, JZ8.0, 1.5 Hz, H-3 ); dC (100 MHz; CDCl3) 39.3,
112.9, 117.9, 118.7 (2C), 123.5, 128.1, 129.8, 132.7, 133.7,
143.7; m/z (EI) 266 (16, MC), 185 (23), 136 (64), 82 (100%).
3.5.3. Oxidation of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-
yl]sulfanyl}acetone with oxonew. To a stirred solution of 2
(0.4 g, 1.4 mmol) in acetone (30 mL) was added dropwise a
solution of oxonew (0.87 g, 2.6 mmol) in water (5 mL). The
mixture was left stirring for 20 min, water (40 mL) was
added and extracted with chloroform (3x30 mL). The
combined organic extracts were dried (Na2SO4) and
evaporated in vacuo to give an oily residue that was purified
by column chromatography (ethyl acetate) to give 1-{[1-(2-
3.6.3. 1-(2-Nitrophenyl)(1H-pyrrol-2-ylsulfinyl)methane
(27). (0.21 g, 68%) as colourless needles (toluene); mp

8814
A. Kimbaris et al. / Tetrahedron 60 (2004) 8807–8815
143–144.5 8C; [Found: C, 52.76; H, 4.05; N, 11.18.
C11H10N2O3S requires C, 52.79; H, 4.03; N, 11.20%];
nmax (Nujol) 3450, 1510, 1230, 1040 cmK1; dH (400 MHz;
CDCl3) 4.79 (1H, d, JZ12 Hz, HCH), 4.85 (1H, d, JZ
12 Hz, HCH), 6.14 (1H, dd, JZ3.7, 2.6 Hz, H-4), 6.43 (1H,
dd, JZ2.6, 1.7 Hz, H-3), 6.97–7.01 (2H, m, H-5, H-60),
7.39–7.46 (2H, m, H-40 kai H-50), 8.06 (1H, dd, JZ8.2,
1.7 Hz, H-30), 11.34 (1H, s, br, NH); dC (100 MHz; CDCl3)
59.5, 109.2, 114.7, 124.8, 125.3, 125.7, 125.8, 129.5, 133.5,
134.0, 148.5; m/z (CI) 268 (100, MCCNH3), 251 (28, MC),
235 (9), 203 (15).
1.4 Hz H-8), 7.61 (1H, ddd, JZ9.0, 8.0, 1.4 Hz, H-10), 7.73
(1H, ddd, JZ9.0, 7.7, 1.6 Hz, H-9), 8.03 (1H, d, JZ8.0 Hz,
H-11); dC (100 MHz; CDCl3) 21.4 (Me), 45.6 (C-5), 65.5
(C-6), 110.1 (C-2), 110.6 (C-3), 115.9 (C-1), 119.8 (C-11),
121.4 (C-3a), 125.0 (C-8), 125.4 (C-10), 129.2 (C-9), 132.9
(C-11a), 146.7 (C-7a); m/z (EI) 248 (32, MCC2), 246 (5,
MC), 173 (61), 157 (55), 131 (17), 84 (83), 49 (100%);
HRMS (EI): (MC), found 246.0825 C13H14N2OS requires
246.0827.
3.8.2. (G)-6-Phenyl-5,6-dihydro-7H-pyrrolo[1,2-a]-
[3.1.6]benzothiadiazocin-7-ol (32). (0.33 g, 56%) as yellow
oil, bp 141–145 8C/12 Torr; nmax (liquid film) 3420 cmK1
;
3.7. Reaction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-
sulfonyl}acetone and 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-
yl]sulfinyl}acetone with sodium hydroxide in aqueous
ethanol
dH (400 MHz; CDCl3) 2.50 (2H, s, br, OH, H-5a), [at 60 8C:
2.55 (1H, dd, JZ13.5, 9.5 Hz, H-5a), 2.69 (1H, dd, JZ13.5,
3.3 Hz, H-5b), 4.57 (1H, dd, JZ9.5, 3.3 Hz, H-6)], 6.36
(1H, dd, JZ3.3, 3.0 Hz, H-2), 6.64 (1H, dd, JZ3.3, 1.7 Hz,
H-3), 6.88 (1H, dd, JZ3.0, 1.7 Hz, H-1), 7.22–7.75 (9H, m,
benzenoid), 8.03 (1H, d, JZ7.1 Hz, H-11); dC (100 MHz;
CDCl3) 46.1 (C-5), 71.3 (C-6), 110.9 (C-2), 120.2 (C-3a),
125.1 (C-3), 125.6 (C-1), 125.9 (4C, benzenoid), 127.8 (1C,
benzenoid), 128.5 (3C, benzenoid), 129.2 (1C, benzenoid),
131.2 (1C, benzenoid), 133.3 (1C, benzenoid), 142.2
(C-7a); m/z (CI) 343 [18, (MCNH4CNH3)C], 340 (100),
272 (20), 221 (20), 187 (57), 171 (24), 107 (21), 83 (39%);
HRMS (ESI): (MCC1), found 309.1052. C18H17N2OS
requires 309.1056.
Compound 13 or 26 (1.2 mmol) was dissolved in ethanol
(15 mL) and treated with a solution of sodium hydroxide
(0.19 g, 4.8 mmol) in water (8 mL) and heated under reflux
over a period of 3 h. After work-up according to General
procedure C, compounds 21 (0.14 g, 46%), 25 (0.14 g, 41%)
or 27 (0.22 g, 72%), prepared by this method, were identical
in all respects to the corresponding compounds obtained by
General procedure D.
3.8. Reductive cyclisation of 1-{[1-(2-nitrophenyl)-1H-
pyrrol-2-yl]sulfanyl}acetone, 2-{[1-(2-nitrophenyl)-1H-
pyrrol-2-yl]sulfanyl}-1-phenylethan-1-one and 2-{[1-(2-
nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetonitrile with
sodium borohydride and 5% palladium-on-carbon.
General procedure E
3.8.3. 6-Amino-5H-pyrrolo[1,2-a][3.1.6]benzothiadia-
zocine-7-oxide (36). (0.21 g, 43%) as yellow powder
(ethyl acetate); mp 94–96 8C [Found: C, 58.75; H, 4.53;
N, 17.12. C12H11N3OS requires C, 58.76; H, 4.52; N,
17.14%]; nmax (Nujol) 3430, 1220 cmK1; dH (400 MHz;
CDCl3) 3.14 (1H, d, JZ12.2 Hz, H-5a), 3.56 (1H, d, JZ
12.2 Hz, H-5b), 3.90 (2H, s, br, NH2), 6.27 (1H, dd, JZ3.6,
3.0 Hz, H-2), 6.57 (1H, dd, JZ3.6, 1.7 Hz, H-3), 6.80 (1H,
dd, JZ3.0, 1.7 Hz, H-1), 7.35–7.55 (3H, m, H-9, H-10 kai
H-11), 7.61 (1H, d, JZ7.7 Hz, H-8); dC (100 MHz; CDCl3)
30.7 (C-5), 109.9 (C-2), 118.2 (C-3), 119.1 (C-3a), 124.0
(C-1), 126.3 (C-11), 127.5 (C-10), 128.2 (C-7), 129.0 (C-6),
129.9 (C-8), 130.6 (C-9), 136.3 (C-11a), 139.1 (C-7a); m/z
(EI) 245 (5, MC), 229 (38), 156 (100), 113 (30), 70 (9%).
A suspension of 5% palladium-on-carbon (0.06 g) in water
(3 mL) was added to a stirred solution of sodium
borohydride (0.3 g, 7.8 mmol) in water (6 mL) while
purging with argon. A solution of 2, 3 or 5 (1.8 mmol) in
1,4-dioxane (20 mL) was added and the mixture stirred for
30 min. After that time an aqueous solution of 2% sodium
hydroxide (18 mL) was added and the mixture was stirred
for 20 min. The reaction mixture was then filtered and the
pH adjusted to 5–6 by the addition of ethanolic hydrogen
chloride. Water (20 mL) was added to the oily solution and
then extracted with dichloromethane (3!20 mL). The
combined organic extracts were dried (Na2SO4) and
evaporated in vacuo, and the oily residue was purified by
column chromatography (20% ethyl acetate/light petroleum)
to give in the first fraction 6-methyl-5,6-dihydro-7H-
pyrrolo[1,2-a][3.1.6]benzothiadiazocin-7-ol 31, 6-phenyl-
5,6-dihydro-7H-pyrrolo[1,2-a][3.1.6]benzothiadiazocin-7-
ol 32 or 6-amino-5H-pyrrolo[1,2-a][3.1.6]benzothiadiazo-
cine-7-oxide 36.
Acknowledgements
This work supported by a PENED grant (91ED102) from
the General Secretariat of Research and Technology, Athens
(to A.K.). We thank Professor N. Hadjiliadis for elemental
analyses, which were obtained on a machine financed by the
Section of Inorganic and Analytical Chemistry of the
University of Ioannina. We are particularly grateful to
A. Cakebread and R. Tye for mass spectra obtained on
machines funded by the University of London Intercollegiate
Research Services Scheme.
3.8.1. (G)-6-Methyl-5,6-dihydro-7H-pyrrolo[1,2-a]-
[3.1.6]benzothiadiazocin-7-ol (31). (0.21 g, 51%) as yellow
oil, bp 136–139 8C/12 Torr; nmax (liquid film) 3400 cmK1
;
dH (400 MHz; CDCl3) 1.10 (3H, d, JZ6.3 Hz, Me), 2.24
(2H, s, br, OH, H-5a), 2.48 (1H, d, JZ12.2 Hz, H-5b), 3.65–
3.70 (1H, m, H-6), [at 60 8C: 2.02 (1H, s, br, OH), 2.35 (1H,
dd, JZ13.2, 8.1 Hz, H-5a), 2.51 (1H, dd, JZ13.2, 4.0 Hz,
H-5b), 3.69 (1H, ddq, JZ8.1, 6.3, 4.0 Hz, H-6)] 6.35 (1H,
dd, JZ3.6, 3.1 Hz, H-2), 6.58 (1H, dd, JZ3.6, 1.7 Hz, H-3),
6.87 (1H, dd, JZ3.1, 1.7 Hz, H-1), 7.55 (1H, dd, JZ7.9,
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